Field of the Invention
The present invention relates to 3-[4-(1H-Benzo[d]imidazol-2-yl)phenyl]-5-phenyl-1,2,4-oxadiazole derivatives of general formula A as anticancer agents. The present invention also relates to a process for the preparation of 3-[4-(1H-Benzo[d]imidazol-2-yl)phenyl]-5-phenyl-1,2,4-oxadiazole derivatives of general formula A.
wherein:R is selected from the group consisting of H, F, Cl, Br, OMe, Me and CF3,R1 is selected from the group consisting of H, 4-F, 4-Cl, 4-Br, 4-CF3, 4-OMe, 3,4-OMe, 3,5-OMe and 3,4,5-OMe, andn is an integer ranging from 1-3.
Background Information
Small molecules have attracted much attention in chemistry, biology and particularly in medicine field for the past few years, which affect tubulin polymerisation. (Jordan, A.; Hadfield, J. A.; Lawrence, N. J.; McGown, A. T. Tubulin as a Target for Anticancer Drugs: Agents which Interact with the Mitotic Spindle. Med. Res. Rev. 1998, 18, 259-296). The targeting of tubulin is an important mechanism for cancer chemotherapy and these tubulin binding agents (taxanes and vinca alkaloids) have played a crucial role in the treatment of diverse human cancers. (Jordan, M. A.; Wilson, L. Microtubules as a target for Anticancer Drugs. Nat. Rev. Cancer 2004, 4, 253-265). Despite of their wide clinical applications, there are several limitations for these derivatives such as poor water solubility, development of drug resistance, toxic effects which has inspired to further search for new effective antitumor agents that target tubulin. Therefore identification of new molecules with tubulin binding mechanism and with minimal toxicity to the normal tissue is attractive for the discovery and development of novel anticancer agents.
Benzimidazole substituted derivatives are known as inhibitors of tubulin polymerisation and are useful for inhibiting cell proliferation for the treatment of cancer. (Vasquez, R. J.; Howell, B.; Yvon, A. M.; Wadsworth, P. Cassimeris, L. Mol. Biol. Cell 1997, 8, 973). Among the anticancer benzimidazoles, an important position is held by 2-aryl/heteroarylbenzimidazole derivatives that are found to be more potent and hence the design and synthesis of 2-aryl benzimidazoles are the potential area of research. (White, A. W.; Almassy, R.; Calvert, A. H.; Curtin, N. J.; Griffin, R. J.; Hostomsky, Z.; Newell, D. R.; Srinivasan, S.; Golden, B. T. J. Med. Chem. 2000, 43, 4084). For instance, Bisbenzimidazole derivatives such as Hoechst 33258 has undergone Phase II clinical evaluation as an anticancer agent and the inhibition of topoisomerase and DNA helicase has been proposed as its mechanism of action. (Singh, M. P., Joseph, T., Kumar, S., Bathini, Y., Lown, J. W., Chem. Res. Toxicol. 1992, 5, 597-607)

Similarly, there has been wide interest in compounds containing the 1,2,4-oxadiazole scaffold because of their broad range of biological activities such as antimicrobial, antiviral, anti inflammatory, and antineoplastic. (Kumar, D.; Patel, G.; Chavers, A. K.; Chang, K. H.; Shah, K. Eur. J Med. Chem. 2011, 46, 3085). Among the oxadiazoles, the 3,5-disubstituted-1,2,4-oxadiazoles derivatives are reported in literature for their anticancer potential. (Jessen, K. A.; English, N. M.; Wang, J. Y.; Maliartchouk, S.; Archer, S. P.; Qiu, L.; Brand, R.; Kuemmerle, J.; Zhang, H. Z.; Gehlsen, K.; Drewe, J.; Tseng, B.; Cai, S. X.; Kasibhatla, S. Mol. Cancer Ther. 2005, 4, 761). References may be made of Journal of pharmaceutical Education and Research 2011, 45, 267” by Mrityunjoy Kundu et al, wherein benzimidazole derivatives as 3,5-Diaryl-1,2,4-Oxadiazole as anticancer agents.
The present inventors have found out that by incorporating 2-aryl benzimidazole with oxadiazole scaffold. enhanced anticancer activity can be achieved that might work through inhibition of tubulin polymerization.